Neuropathic pain and in inflammation

Injuries of peripheral nerves can cause chronic inflammation in the dorsal horn of the spinal cord as well as in the pain pathways to the thalamus and the cortex. Glia plays an important role!

The inflammation reaction in the CNS is due to activation of glial cells. Glia cells are transformed into reactive microglia, which in turn activates astrocytes. Activated astrocyte leads to formation of new synapses. The editors describe this proces elegantly:

'New neuronal contacts are formed that maintain and spread neurosignals, with the pain-sensation-mediating astrocytic networks acting as bridges. These processes, in which activated glia cells play important parts, may contribute to the explanation of how acute or sub-acute pain sensations can become long-term and how they can be experienced in other parts of the body than where the original injury occurred'

However, after years of neuropathic pain many other pathogenetic pathways in the body are activated:

'The changes that occur due to longstanding activation of microglia and the astrocyte networks may become irreversible, in part due to death of neurones in the spinal cord from apoptosis and excitotoxic processes. It may therefore be too much to hope for that immunosuppressive therapy will have any effect at in late stages of chronic complex pain conditions. Multiple other mechanisms will also have been involved in neuropathic pain that has lasted for years...'

But clearly the editors put their vinger on the sour place: a muti-pathogenetic network forms the basis to understand chronic neuropathic pain, and no magic bullets will emerge based on one mechanism only.

The same focus we find in a lecture of the Japanese anesthesiologist T. Kohno, and we quote from his article on Neuropathic pain and neuron–glia interactions in the spinal cord:^[1]

To date, basic research on neuropathic pain has tended to focus on injury-induced changes in nociceptive and spinal cord neurons that receive sensory information before it is relayed to the brain. This is the reason why it was believed that neuropathic pain was purely a matter of miscommunication between neurons. However, recent work shows that nerve injury-induced changes also occur in spinal glial cells, the immune cells of the CNS, and the importance of glial biology in neuropathic pain now seems undeniable. 

He too adresses the role of microglia and asterocytes, and foresees new targets for the treatment of neuropathic pain in this direction:

In addition to microglia, accumulating evidence has also identified a role for astrocyte-specific molecules in neuropathic pain, and demonstrated a critical role of spinal astrocytes in this type of pain, in particular in the maintenance phase . How these two distinct groups of glial cells interact with each other is now open for investigation. It is expected that increased understanding of the functions of glial molecules will provide us with exciting insights into pain mechanisms and clues to developing new therapeutic agents for the management of neuropathic pain. 

Cannabinoids? Low dose naltrexone? 

Glia, asterocytes and modulation of inflammatory responses are hot in the search for new treatments for neuropathic pain. ^{[2] [3][4][5]} And not only the cannabinoids might work via this mechanism, ^[6] even low dose naltrexone, popular at the time in patients suffering from MS ^[7], might play a role in this pathogenesis. ^[8][9]

The later is quite interesting, it provokes us to rethink the putative role of low dose naltrexone in the treatment of neuropathic pain... ^[10][11][12]

Let us review the only trial I know assessing the effects of low dose naltrexone in a sort of neuropathic pain: fibromyalgia. 

Naltrexone low dose: a pilot trial

Recently a pilot trial was reported on the efficacy and safety of low dose naltrexone (5 mg) in fibromyalgia. Especially patients with a high ESR were found to be responders to the naltrexone theraoy. That is quite fitting with the above hypothesis. Especially since we know patients suffering from fibromyalgia pain also respond positive tp pregabeline.  The authors of the report, Younger and Mackey, conducted a placebo-controlled, single-blind, crossover design study in 10 patients with moderately-severe fibromyalgia, and the dose was 4-5 mg/day.

Naltrexone treatment resulted in 32.5% decrease of overall fibromyalgia symptom severity on the visual analog scale compared with baseline, whereas the reduction was only 2.3% during the placebo phase (P<0.0005 versus baseline and P=0.003 versus placebo). ^[13] More details on the site of Stanford.

And the same dose seemed to inhibit the symptoms of Crohn's disease..^[14]

May 2010, Jan M. Keppel Hesselink, MD, PhD 

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